Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Departments of Pediatrics and Surgery, University of Alberta, Edmonton, Alberta, Canada.
Am J Physiol Heart Circ Physiol. 2012 May 1;302(9):H1784-94. doi: 10.1152/ajpheart.00804.2011. Epub 2012 Mar 9.
During the neonatal period, cardiac energy metabolism progresses from a fetal glycolytic profile towards one more dependent on mitochondrial oxidative metabolism. In this study, we identified the effects of cardiac hypertrophy on neonatal cardiac metabolic maturation and its impact on neonatal postischemic functional recovery. Seven-day-old rabbits were subjected to either a sham or a surgical procedure to induce a left-to-right shunt via an aortocaval fistula to cause RV volume-overload. At 3 wk of age, hearts were isolated from both groups and perfused as isolated, biventricular preparations to assess cardiac energy metabolism. Volume-overload resulted in cardiac hypertrophy (16% increase in cardiac mass, P < 0.05) without evidence of cardiac dysfunction in vivo or in vitro. Fatty acid oxidation rates were 60% lower (P < 0.05) in hypertrophied hearts than controls, whereas glycolysis increased 246% (P < 0.05). In contrast, glucose and lactate oxidation rates were unchanged. Overall ATP production rates were significantly lower in hypertrophied hearts, resulting in increased AMP-to-ATP ratios in both aerobic hearts and ischemia-reperfused hearts. The lowered energy generation of hypertrophied hearts depressed functional recovery from ischemia. Decreased fatty acid oxidation rates were accompanied by increased malonyl-CoA levels due to decreased malonyl-CoA decarboxylase activity/expression. Increased glycolysis in hypertrophied hearts was accompanied by a significant increase in hypoxia-inducible factor-1α expression, a key transcriptional regulator of glycolysis. Cardiac hypertrophy in the neonatal heart results in a reemergence of the fetal metabolic profile, which compromises ATP production in the rapidly maturing heart and impairs recovery of function following ischemia.
在新生儿期，心脏能量代谢从胎儿糖酵解模式向更依赖于线粒体氧化代谢的模式发展。在这项研究中，我们确定了心脏肥大对新生儿心脏代谢成熟的影响及其对新生儿缺血后功能恢复的影响。7 日龄的兔子接受假手术或手术处理，通过主动脉-腔静脉瘘引起左向右分流，导致 RV 容量超负荷。在 3 周龄时，从两组中分离心脏，并作为离体、双心室制剂进行灌注，以评估心脏能量代谢。容量超负荷导致心脏肥大（心脏质量增加 16%，P < 0.05），但在体内和体外均无心脏功能障碍的证据。脂肪酸氧化率在肥大心脏中降低了 60%（P < 0.05），而糖酵解增加了 246%（P < 0.05）。相比之下，葡萄糖和乳酸氧化率没有变化。肥大心脏的总 ATP 产生率显著降低，导致有氧心脏和缺血再灌注心脏中的 AMP-to-ATP 比值增加。肥大心脏能量生成降低抑制了缺血后的功能恢复。由于丙二酰辅酶 A 脱羧酶活性/表达降低，脂肪酸氧化率降低的同时伴有丙二酰辅酶 A 水平升高。肥大心脏中糖酵解的增加伴随着缺氧诱导因子-1α表达的显著增加，这是糖酵解的关键转录调节因子。新生儿心脏中的心脏肥大导致胎儿代谢模式重新出现，这会损害快速成熟的心脏中的 ATP 产生，并损害缺血后的功能恢复。
